Babygirija Reji, Sonsalla Michelle M, Mill Jericha, James Isabella, Han Jessica H, Green Cara L, Calubag Mariah F, Wade Gina, Tobon Anna, Michael John, Trautman Michaela M, Matoska Ryan, Yeh Chung-Yang, Grunow Isaac, Pak Heidi H, Rigby Michael J, Baldwin Dominique A, Niemi Natalie M, Denu John M, Puglielli Luigi, Simcox Judith, Lamming Dudley W
Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
Res Sq. 2024 Apr 24:rs.3.rs-3342413. doi: 10.21203/rs.3.rs-3342413/v2.
Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain metabolome and lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
膳食蛋白质是代谢健康和衰老的关键调节因子。低蛋白饮食与人类健康衰老相关，许多独立的研究团队已表明，膳食蛋白质限制（PR）可延长小鼠的寿命和健康寿命。在此，我们研究了PR对阿尔茨海默病（AD）3xTg小鼠模型的代谢健康以及AD发生和进展的影响。我们发现，PR对3xTg小鼠和两性非转基因对照小鼠均有代谢益处，可促进3xTg小鼠的瘦体重和血糖控制，并改善3xTg雌性小鼠的葡萄糖不耐受。我们发现，PR会引起循环代谢物以及大脑代谢组和脂质组的性别特异性改变，下调3xTg雌性小鼠中包括神经酰胺、葡萄糖神经酰胺和鞘磷脂在内的鞘脂亚类。6个月大开始食用PR饮食可减少AD病理，同时降低mTORC1活性、增加自噬，并对3xTg小鼠具有认知益处。最后，PR提高了3xTg小鼠的存活率。我们的结果表明，PR在分子和病理水平上减缓了AD的进展，在该AD小鼠模型中保留了认知功能，并表明PR或模拟这种饮食效果的药物干预可能有望成为AD的一种治疗方法。
